Search

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry (https://www.clinicaltrialsregister.eu): EudraCT: 2014-005341-44 [ABSTRACT FROM AUTHOR]

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema (n = 7, 18.9%) followed by pruritis and nausea (n = 5, 13.5%, each), fatigue, anemia, and decreased appetite (n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224 [ABSTRACT FROM AUTHOR]